Epilepsy Research (2012) 98, 251—254
journal homepage: www.elsevier.com/locate/epilepsyres
Diffusion tensor imaging of subependymal heterotopia C. Briganti a, R. Navarra a, C. Celentano b, B. Matarrelli b, A. Tartaro a, G.L. Romani a, M. Caulo a,∗ a b
Department of Neuroscience and Imaging, University ‘‘G. D’Annunzio’’, Chieti, Italy Clinica Ostetrica-Ginecologica, University ‘‘G. D’Annunzio’’, Chieti, Italy
Received 5 April 2011; received in revised form 30 August 2011; accepted 1 September 2011 Available online 25 September 2011
KEYWORDS Subependymal heterotopia; Magnetic resonance imaging; Diffusion tensor imaging
Summary A magnetic resonance (MR) diffusion tensor imaging (DTI) study was performed in a newborn with bilateral subependymal heterotopia (SE). White matter fractional anisotropy (FA), axial diffusivity (AD) and radial diffusivity (RD) were compared to values obtained in four newborns with moderate perinatal asphyxia and normal MRI ﬁndings. The reduction of FA and increase of AD and RD in the newborn with SE were the in vivo late expression of alterations in the intermediate zone, with an underlying arrest of neuronal migration. © 2011 Elsevier B.V. All rights reserved.
Introduction Subependymal heterotopia (SE) is a malformation of cortical development in which a premature arrest of neuronal radial migration from the germinal matrix to the cerebral cortex determines the formation of multiple subependymal heterotopic gray matter nodules (Barkovich and Kjos, 1992; Mitchell et al., 2000; Guerrini and Parrin, 2010). In normal conditions, neurons migrate from subventricular and ventricular zones (germinal matrix) across intermediate zone (IZ) to the cortical plate. The IZ contains radial glial cells that support neuronal radial migration, a precursor of neonatal white matter (Bystron et al., 2008). Using diffusion tensor magnetic resonance imaging (DTI) we aimed at evaluating the microstructural organization of the
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white matter in a newborn with SE in order to demonstrate in vivo the presence of an underlying white matter alteration (Johansen-Berg and Behrens, 2009).
Case report A 38-year-old pregnant woman with an uneventful previous pregnancy and no relevant medical history was referred for a detailed fetal morphologic sonographic scan and MRI following a routine ultrasound which suggested the presence of dilated cisterna magna. The patient underwent Chorionic Villous Sampling (CVS) demonstrating normal female karyotype (46,XX). Fetal ultrasound and MRI at 27 weeks of gestation demonstrated the presence of a megacisterna magna and an irregular appearance of the ependymal surface of the lateral ventricles due to the presence of small nodules having the same ultrasound characteristics and MRI
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C. Briganti et al.
Figure 1 Fetal sonographic (A) and axial MRI T2-weighted (B) images obtained at 27 weeks of gestation showing an irregular ependymal surface of the lateral ventricles (white arrows). Axial T2- (C) and T1-weighted (D) MR images obtained 2 weeks after birth demonstrate the presence of multiple heterotopic gray matter nodules along the walls of the lateral ventricles.
signal intensity as the superﬁcial layer of the brain, therefore suggesting the presence of SE (Fig. 1A and B). Pregnancy remained uneventful, and a Cesarean section was performed at 38 weeks of gestation. Apgar score at 1 and 5 was 8 and 9, respectively and neurological examination was normal. The neonatal period was clinically uneventful. The newborn was evaluated using formal neuropsychological tools: the Mental Developmental Index and Psychomotor Developmental Index of the Bayley Scale of Infant Development II. Both were within normal range (Black and Matula, 1999). The parents received extensive genetic counseling and initially gave their consent for the Xq28 genetic test but subsequently refused once the sample was collected. Two weeks after delivery, an MRI brain study was performed using a 3 T system (Achieva, Philips Medical Systems, Best, The Netherlands) which included anatomical T1and T2-weighted sequences. The presence of multiple, subependymal nodules in the lateral ventricles conﬁrmed the pre-natal diagnosis of SE (Fig. 1C and D). A normal for age MRI pattern of myelination of the posterior limb
of the internal capsule and dorsal brainstem was also highlighted (Barkovich, 2005). In addition to standard MRI sequences, DTI was performed using 32-different diffusion gradient directions. DTI data were processed using the FSL (Analysis Group FMRIB, Oxford, United Kingdom). Fractional anisotropy (FA), axial diffusivity (AD) and radial diffusivity (RD) values of the supra-tentorial white matter were calculated. These values were compared with those obtained from four full-term newborns with moderate perinatal asphyxia scanned within two weeks from birth and presenting normal MRI ﬁndings including diffusion weighted imaging (DWI). Since DWI is highly sensitive to recent hypoxic—ischemic lesions, the absence of gray and white matter abnormalities reinforced our conclusion concerning the integrity of the white matter of controls. Differences in values were expressed as standard deviations and two-sided conﬁdence intervals (CI). The AD and RD were higher in the newborn with SE than in the group of normal newborns: 0.002610 vs. 0.002278 ± 0.000066 (45.01 SD; 99.99% CI) and 0.000900 vs. 0.000768 ± 0.000036 (3.54 SD; 99.96% CI), respectively. The FA was reduced in the
Diffusion tensor imaging of subependymal heterotopia
Figure 2 Schematic diagram representing a normal hemisphere (left) and a hemisphere with altered white matter and periventricular heterotopic gray matter nodules (right). Bars represent mean FA, AD and RD with standard deviation in the white matter of the four controls (left) and of the newborn with SE (right).
newborn with SE compared with control newborns: 0.1630 vs. 0.1788 ± 0.0221 (0.72 SD; 52.85% CI) (Fig. 2).
Discussion SE is a cortical malformation, which may be isolated or associated with other brain disorders (megacisterna magna, callosal agenesis, polymicrogyria, Chiari II malformations, and cerebellar hypoplasia) (Mitchell et al., 2000). Most of the bilateral forms of SE follow an X-linked dominant inheritance pattern with a gene located in Xq28: the ﬁlamin A (FLNA) (Guerrini and Parrin, 2010; Bargallò et al., 2002). The product of the FLNA gene is a phosphoprotein inducing actin reorganization which triggers nerve growth along the radial glial cells. A mutation induces failure of the neuronal motility causing premature arrest of neuronal migration. Another possible, less frequent mutation in SE, concerns ADP-ribosylation factor guanine exchange factor 2 (ARFGEF2) gene which encodes Brefeldin A-inhibited guanine nucleotide-exchange factor 2 (BIG2), a regulator of neuronal precursor proliferation (Ferland et al., 2009). This mutation induces neuro-ependymal damage causing an unsuccessful migration of later-born neurons resulting in the formation of heterotopic gray matter nodules (Ferland et al., 2009). In summary, SE is a migratory disorder which can be secondary to the impairment of neuronal motility substrate or arise from a disruption in neural progenitors that inﬂuences migration of later-born neurons. DTI assesses random motion of water molecules within biologic tissue and is frequently used to study neurological diseases since it can provide insight into white
253 matter microstructure and development, reﬂecting underlying tissue abnormalities (speciﬁcally the white matter) (Johansen-Berg and Behrens, 2009). In the newborn with SE DTI ﬁndings seem to move toward the ﬁrst aforementioned pathogenetic theory demonstrating the presence of an altered white matter organization resulting in increased AD and RD values. RD parameters provide speciﬁc information about axonal integrity. In particular, increased RD was considered a marker of the overall tissue integrity representing either demyelination or axonal damage (Klawiter et al., 2011). Whether demyelination, axonal damage or a combination of these two pathological conditions determines an increase of RD is unpredictable solely on the basis of the DTI.However, DTI data showed an impairment of neuronal motility substrate that could be explained by an alteration of radial glial ﬁbers which could determine, together with the neurons, abnormal migration of the oligodendrocyte progenitors. These progenitors are present in a gradient from the subventricular zone to the cortical plate and their close apposition to radial glia ﬁbers suggests a possible role of glia ﬁbers in oligodendrocyte migration (Jakovcevski and Zecevic, 2005). The increased RD in the SE newborn could be the expression of a reduced myelination of white matter ﬁbers and the demonstration of the hypothesis that SE is a disorder involving the migratory substrate of neurons and oligodendrocytes. The presence of an increased RD together with increased AD likely negated their effect on FA, which was not signiﬁcantly reduced in the SE newborn. The increase in AD (also referred to as parallel diffusion) may be justiﬁed by the neuropathological demonstration of a disruption of the radial glial organization surrounding the heterotopic periventricular nodules (Santi and Golden, 2001), which would decrease the complexity of the extra-axonal space. In this study we demonstrated that a newborn with bilateral SE had microstructural white matter alterations. In the SE newborn we considered the increase of the RD and AD as the in vivo expression of axonal and glial alterations, respectively.
Acknowledgment The authors thank Dr. Peter A. Mattei for his help in editing the ﬁnal version of the manuscript.
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